Abstract 3949: Dynamic Regulation and Metabolic Functions of Lipin 1 in the Heart
Lipin 1 is an intracellular protein that acts in the nucleus to coactivate expression of genes involved in fatty acid oxidation (FAO) and at the endoplasmic reticulum to catalyze the conversion of phosphatidate to diacylglycerol in the triglyceride (TG) synthesis pathway. Although lipin 1 is highly enriched in the heart, little is known regarding the regulated expression and function of lipin 1 in cardiac myocytes. PGC-1α is a transcriptional coactivator that plays a critical role in controlling cardiac fatty acid metabolism. PGC-1α overexpression increased lipin 1 gene expression in transgenic mouse heart and in isolated cardiac myocytes. Consistent with this, swimming exercise and the β-adrenergic agonist clenbuterol induced PGC-1α activity and also increased cardiac lipin 1 expression 4.6-fold and 1.9-fold, respectively. However, compensated and decompensated pathologic cardiac hypertrophy, which are associated with down-regulation of PGC-1α, led to reduced cardiac lipin 1 expression [43% (p<0.01) and 34% (p<0.05), respectively]. Studies conducted in neonatal rat ventricular myocytes supported the idea that both molecular functions of lipin were operative in cardiac myocytes. Specifically, adenovirus-mediated lipin 1 overexpression increased, whereas shRNA-mediated knockdown of lipin 1 down-regulated, expression of genes encoding enzymes involved in FAO (Cpt1b and Acadm). Furthermore, in the presence of high levels of oleate (0.5 mM), lipin 1 overexpression stimulated TG synthesis 2-fold (p<0.01) as assessed by 3H-glycerol incorporation in TG. In contrast, lipin 1 knockdown significantly attenuated the oleate-induced increase in TG synthesis rates. Interestingly, baseline cardiac TG content was unchanged in mice completely deficient in lipin 1 (fld mice) compared to wild-type (WT) littermates. However, a bolus (7 μl/g body wt) of olive oil administered by gavage increased cardiac TG levels in WT (p<0.05), but not fld mice. In conclusion, lipin 1 is dynamically regulated by physiologic and pathophysiologic stimuli in the heart and may play a critical role in regulating cardiac FAO gene expression and TG synthetic capacity.